Bleeding Pseudocyst of the Pancreatic Head. The role of Omentoplasty and Local Hemostasis

Treatment of bleeding psedoaneurysms and pseudocysts of the pancreas is controversial. Surgical treatment with pancreatic resection or trancystic arterial ligation is not always satisfactory since postoperative mortality rate is high, especially for lesions located in the pancreatic head and rebleeding is not unusual. Two patients with bleeding pseudoaneurysms (one post traumatic, one spontaneous) and one with a hemorrhagic pseudocyst of the pancreatic head were treated surgically with arterial suture and omentoplasty. Bleeding was controlled in all, without any postoperative mortality or morbidity. No rebleeding occurred with a follow up of 33, 26 and 12 months. Trancystic ligation of bleeding vessels with omentoplasty may be a useful approach, which should be compared to arterial embolization in the future

Thérapie génique suicide des métastases hépatiques des cancers colorectaux

Le carcinome colorectal est l'un des cancers les plus fréquents en France et les métastases, observées dans 40 à 60% des cas, sont généralement responsables du décès des patients. La résection chirurgicale reste aujourd'hui le seul traitement curatif des métastases hépatiques, mais 10% des cas peuvent bénéficier. La thérapie génique suicide consiste à transférer dans les cellules tumorales, un gène viral ou bactérien, appelé gène "suicide", dont le produit est capable de convertir une prodrogue non toxique en drogue létale. Ainsi, le gène cytosine désaminase (CD) permet de convertir la 5-fluorocytosine, prodrogue non toxique en 5-fluorouracile, drogue cytotoxique. Dans un premier temps, nous avons utilisé une approche de vaccination par injection intra-hépatique ou sous-cutanée de cellules tumorales autologues exprimant le gène CD dans un modèle syngénique de métastases hépatiques de cancer colique chez le rat. Nous avons observé un puissant effet bystander à distance permettant d'induire la régression de métastases hépatiques préexistantes et d'augmenter significativement de la survie de rats porteurs de métastases uniques ou multiples. Nous avons ensuite développé une approche nous permettant d'utiliser ce type de stratégie en clinique. Pour cela, nous avons analysé l'effet thérapeutique d'une injection intratumorale d'un plasmide exprimant le gène CD, suivie d'un traitement par 5-FC. Nous avons ainsi montré, chez des animaux porteurs de tumeurs hépatiques sauvages sur les lobes gauche et droit du foie, que l'injection d'un plasmide exprimant le gène CD dans l'une des 2 tumeurs conduisait à une diminution de 70% du volume médian de l'ensemble des lésions après traitement par 5-FC. Suite au traitement, une augmentation de la résécabilité des tumeurs hépatiques et de la survie était observée dans les 2 modèles.Colon carcinoma represents one of the more frequent cancers in westernized countries and is associated with a high mortality, due to the appearance of metastasis preferentially located to the liver. As resection of metastasis, which constitutes the only curative treatment, is applicable in only 10 to 20% of the patients, many efforts are dedicated to the development of alternative treatments such as gene therapy. Suicide gene therapy consists in the transfer into tumor cells of a killer gene converting a non-toxic compound, that can be systemically administered, into a lethal drug. The bacterial cytosine deaminase (CD) gene, that is not expressed in mammals, encodes for an enzyme capable of converting cytosine into uracil. When expressed in mammalian cells, this enzyme can transform the non-toxic antifungal agent 5-fluorocytosine (5-FC), into the widely used chemotherapeutic drug 5-fluorouracil (5-FU). We first developed a vaccination strategy by injecting CD-expressing (CD+) autologous tumor cells to trigger an antitumor immune reaction. Using a syngenic rat liver metastasis model, we have shown that intra-hepatic injection of CD+ tumor cells followed by 5-FC treatment of the animals, resulted in the destruction of the suicide cancer cells. In addition, following this suicide cell-based vaccination, the animals became resistant to the development a new wild-type tumor, indicating the establishment of an antitumor immune response. We have also demonstrated that this vaccination induced a distant bystander effect resulting in the regression of wild-type pre-established tumors and increased the survival of the animals. Finally, we have analyzed the antitumor efficiency of a direct intratumoral injection of a CD-expressing plasmid. In rats bearing microscopic or macroscopic metastases in right and left liver lobes, an injection of a CD-expressing plasmid was performed in the left lobe tumor, followed by 5-FC treatment of the animals. A significant regression of the DNA-injected tumor was observed in 5-FC-treated rats, both in microscopic or advanced tumor models. Moreover, this treatment also induced a potent distant bystander effect on untreated controlateral liver tumors and extra-hepatic metastases, resulting in an increased survival compared to control animals in both tumor models.NICE-BU Sciences (060882101) / SudocSudocFranceF

Comparative Proteomics Study Reveals That Bacterial CpG Motifs Induce Tumor Cell Autophagy in Vitro and in Vivo

International audienceUnmethylated CpG dinucleotides, present in bacterial DNA, are recognized in vertebrates via the Toll-like receptor 9 (TLR9) and are known to act as an anticancer agent by stimulating immune cells to induce a proinflammatory response. Although the effects of CpG-oligodeoxynucleotides (CpG-ODNs) in immune cells have been widely studied, little is known regarding their molecular effects in TLR9-positive tumor cells. To better understand the role of these bacterial motifs in cancer cells, we analyzed proteome modifications induced in TLR9-positive tumor cells in vitro and in vivo after CpG-ODN treatment in a rat colon carcinoma model. Proteomics analysis of tumor cells by two-dimensional gel electrophoresis followed by mass spectrometry identified several proteins modulated by bacterial CpG motifs. Among them, several are related to autophagy including potential autophagic substrates. In addition, we observed an increased glyceraldehyde-3-phosphate dehydrogenase expression, which has been shown to be sufficient to trigger an autophagic process. Autophagy is a self-digestion pathway whereby cytoplasmic material is sequestered by a structure termed the autophagosome for subsequent degradation and recycling. As bacteria are known to trigger autophagy, we assessed whether bacterial CpG motifs might induce autophagy in TLR9-positive tumor cells. We showed that CpG-ODN can induce autophagy in rodent and human tumor cell lines and was TLR9-dependent. In addition, an increase in the number of autophagosomes can also be observed in vivo after CpG motif intratumoral injection. Our findings bring new insights on the effect of bacterial CpG motifs in tumor cells and may be relevant for cancer treatment and more generally for gene therapy approaches in TLR9-positive tissues